Clinical Significance of Cancer Stem Cell Markers in Primary and Metastatic Tissues in Patients With Breast Cancer.

BACKGROUND/AIM: This study aimed to examine the clinical significance of the protein expression of the cancer stem cell (CSC) markers ALDH1A1, CD133, CD44, and MSI-1 in primary and metastatic tissues of patients with breast cancer (BC). PATIENTS AND METHODS: ALDH1A1, CD133, CD44, and MSI-1 protein expression in pairs of primary and metastatic tissues of 55 patients with BC with metastases treated at Kanagawa Cancer Center between January 1970 and December 2016 were evaluated using immunohistochemical assay and their association with clinicopathological factors and survival was examined. RESULTS: There were no significant differences in CSC marker expression rates between primary and metastatic tissues for any CSC markers. Regarding the relationship between CSC marker expression in primary tissues and survival, patients with high CD133 expression had significantly lower recurrence-free survival (DFS) and overall survival. On multivariate analysis, they were also a poor independent predictor of DFS (hazard ratio=4.993, 95%CI=2.189-11.394, p=0.0001). In contrast, there was no significant association between the expression of any CSC marker in metastatic tissues and survival. CONCLUSION: CD133 expression in the primary BC tissue may be a useful risk factor for recurrence in patients with BC.

Ovarian goiter detected during post-operative follow-up of papillary thyroid cancer: a case report.

A 70-year-old female without any past medical history underwent total thyroidectomy and central neck dissection for papillary thyroid cancer (PTC) (pT3bN1aM0 pStage II). Her post-operative thyroglobulin (Tg) level remained high (around 100 ng/mL), which increased to 366 ng/mL 5 years after surgery. Computed tomography revealed metastasis to the left III and right Vb and VI lymph nodes and an incidental ovarian tumor. Transvaginal ultrasonography and magnetic resonance imaging suspected malignancy, resulting in total hysterectomy and bilateral adnexal resection. A pathological diagnosis of ovarian goiter with no malignancy was then established. For lymph node metastasis of PTC, right neck dissection and left III lymph node resection were performed. Post-operative blood examination showed a significant decrease in the Tg level (5.9 ng/mL). In conclusion, systemic imaging or I-131 remnant ablation should be performed after total thyroidectomy, as evident in the present case in which Tg levels did not decrease after total thyroidectomy.

Lung cavitation in patients with anaplastic thyroid cancer treated with lenvatinib.

Background: Anaplastic thyroid cancer (ATC) is a rare malignancy with a poor prognosis. It accounts for 1-2% of all thyroid cancers. Lenvatinib is an orally administered inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, fibroblast growth factor receptor (FGFR)-1 to -4, platelet-derived growth factor receptor (PDGFR)-α, rearranged during transfection (RET), and KIT. There have been cases of pneumothorax caused by lung cavitation and collapse after administration of lenvatinib in ATC with lung metastasis. In this study, we investigate lung cavitation during treatment with lenvatinib in ATC patients with lung metastasis. Methods: All ATC patients with lung metastasis treated at our hospital with lenvatinib between November 2015 and May 2021 were selected from our electronic medical records. The primary objective was to determine the incidence of cavitation of lung metastasis of ATC in patients treated with lenvatinib. The secondary objective was to evaluate prognostic factors in ATC patients with lung metastasis treated with lenvatinib. Results: We identified 26 patients treated with lenvatinib for ATC with lung metastasis. Of these, 12 (46.2%) had cavitation with lung metastasis during lenvatinib treatment. The median overall survival (OS) was 128 days (79-228 days), and the cavitation (+) group had significantly longer OS than the cavitation (-) group [186 days (117-355 days) vs. 89 days (59-179 days), P=0.033]. Kaplan-Meier survival curves indicated a significant difference in OS was observed between the two groups (P=0.0293). Univariate analysis demonstrated lung cavitation was a significant prognostic factor (hazard ratio: 0.38, 95% CI: 0.16-0.93). Conclusions: Lung cavitation occurred in 46.2% of patients treated with lenvatinib for ATC with lung metastasis. Patients who developed lung cavitation had a significantly better prognosis than those who did not.

Hyperthyroidism due to thyrotropin receptor antibody stimulation of metastatic thyroid carcinoma during lenvatinib treatment: a case report.

BACKGROUND: Hyperthyroidism after total thyroidectomy is extremely rare. No studies have investigated hyperthyroidism during multiple kinase inhibitor treatment for advanced thyroid carcinoma. CASE DESCRIPTION: A 57-year-old man with a history of radioactive iodine refracted thyroid follicular carcinoma presented to our hospital with back pain. Computed tomography (CT) showed a huge tumor at the left ilium and multiple metastases in the lung, liver, and bone. His serum thyroglobulin was 322,000 ng/mL and bone biopsy revealed thyroid carcinoma metastasis. After left iliac tumor decompression surgery, lenvatinib and denosumab treatment were initiated. Serum thyroglobulin decreased to 88,600 ng/mL, and no progression was observed on CT. Although thyrotropin (TSH) was suppressed at 125 µg of levothyroxine sodium, serum free T3 started to increase at 70 weeks after lenvatinib initiation. Levothyroxine sodium was gradually reduced to 25 µg. At 83 weeks after initiation, the patient was hospitalized due to nausea, diarrhea, and anorexia. Serum free T3 increased to 13.98 pg/mL, whereas CT showed progression of lung and liver metastasis. Given the patient's positivity for anti-thyrotropin receptor antibody (TRAb), levothyroxine sodium and lenvatinib were discontinued and methimazole was administered at the dose of 15 mg/day. Lenvatinib was restarted after 2 weeks withdrawal. Methimazole was gradually reduced to 5 mg/day as thyroid function normalized. However, CT showed pleural effusion and enlargement of the lung, liver, and adrenal metastases. The patient died at 100 weeks after lenvatinib initiation due to disease progression. CONCLUSIONS: The patient developed Graves' disease after lenvatinib treatment for radioactive iodine refracted thyroid follicular carcinoma. Persistent TSH stimulation caused by TRAb can be involved in tumor growth and thyroid hormone secretion from metastases.

Effect of Vandetanib Treatment on Cystic Changes in the Liver following Metastasis from Medullary Thyroid Carcinoma.

A number of causes are responsible for the development of cystic lesions in the liver. However, metastasis is a rare cause, and cystic metastasis from medullary thyroid carcinoma has not yet been reported. A 46-year-old Japanese man presented to our hospital with a mass in the left side of his neck. Neck and thyroid ultrasonography revealed a thyroid tumor with calcification and enlarged cervical lymph nodes. He had a family history of medullary thyroid cancer. Computed tomography revealed a tumor in the thyroid and multiple cysts in the liver. Total thyroidectomy with modified neck and upper mediastinum dissections were performed. After surgery, vandetanib treatment was initiated owing to tumor progression; following this, the liver cysts increased in size, abdominal distension appeared, and serum liver enzyme levels were found to be elevated. Percutaneous liver cyst puncture was performed to reduce abdominal distension; however, it was ineffective. The liver enzyme levels improved after replacing vandetanib with lenvatinib treatment. The liver cysts in this case were indicated to be associated with medullary thyroid carcinoma.

TROP-2, Nectin-4, GPNMB, and B7-H3 Are Potentially Therapeutic Targets for Anaplastic Thyroid Carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a highly aggressive thyroid tumor with a poor prognosis. However, there are limited choices for ATC treatment. Recently, the effectiveness of antibody-drug conjugates has been demonstrated in various carcinomas. Whether the targets of antibody-drug conjugates are expressed in anaplastic thyroid carcinoma remains unclear. METHODS: Fifty-four patients with ATC were enrolled in this study. Tissue microarrays were constructed using the archives of formalin-fixed paraffin-embedded tissue blocks. All sections were stained with the following antibody-drug conjugate targets: human epidermal growth factor receptor 2 (HER2), nectin-4, trophoblast cell surface antigen 2 (TROP-2), glycoprotein non-metastatic B (GPNMB), and B7-H3. RESULTS: HER2 was negative in all tissues, whereas GPNMB and B7-H3 were expressed in most ATC tissues. TROP-2 and nectin-4 were expressed in 65% and 59% of ATC tissues, respectively. TROP-2 was expressed at significantly higher levels in ATC undifferentiated from papillary thyroid carcinoma than in ATC undifferentiated from follicular thyroid carcinoma and de novo ATC. In contrast, nectin-4 expression was markedly higher in patients with de novo ATC than in those with papillary and follicular thyroid carcinoma. CONCLUSIONS: TROP-2 and nectin-4 are potential therapeutic targets for ATC undifferentiated from papillary thyroid carcinoma and de novo ATC, respectively. GPNMB and B7-H3 potential for treating all types of ATC.

Simultaneous nodular lymphocyte-predominant Hodgkin lymphoma with papillary thyroid carcinoma: a case report.

We herein report the case of a 48-year-old man diagnosed with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL, Stage IA) and papillary thyroid carcinoma (PTC, Stage I). Total thyroidectomy, left modified neck dissection and biopsy of the right cervical lymph node were performed. Postoperatively, NLPHL treatment was prioritized, and external radiation (30.6 Gy) was applied to the right neck. PTC was considered a high-risk category for recurrence due to extranodal invasion of lymph node metastasis, and radioactive iodine therapy (ablative dose, 1110 MBq) was administered. Both PTC and NLPHL showed no recurrence 18 months after surgery.

Pulmonary cavitation in a patient with coronavirus disease 2019 during lenvatinib treatment for thyroid carcinoma: a case report.

Lenvatinib, a multi-tyrosine kinase inhibitor, is used for the treatment of thyroid carcinoma. However, it can cause pneumonia and pulmonary cavitation leading to pneumothorax. The mechanism underlying the occurrence of cavitation and pneumothorax is not well understood. Coronavirus disease 2019 (COVID-19), which is an infectious condition characterized primarily by pneumonia, is sometimes accompanied by pulmonary cavitation. Patients with COVID-19 who present with pulmonary cavitation may have a poor prognosis. In the present case, a patient with papillary thyroid carcinoma presented with multiple pulmonary metastatic tumors that were treated with lenvatinib. After 9 weeks from treatment initiation, he experienced fever and presented with pulmonary consolidation and ground-glass opacity (GGO). Pneumonia improved after the withdrawal of lenvatinib. After 21 weeks from treatment initiation, he developed fever again and the clinical tests led to the diagnosis of COVID-19. Computed tomography (CT) showed new GGO in both sides of the lung. Therefore, the patient was diagnosed with moderate COVID-19. He was treated with dexamethasone plus remdesivir, and GGO due to COVID-19 disappeared. However, the previous pulmonary shadow associated with lenvatinib became a cavitary lesion. The initial CT findings of COVID-19 and pneumonia associated with lenvatinib are similar. Thus, both conditions must be considered for a differential diagnosis in patients presenting with GGO during lenvatinib treatment.

Pneumatosis intestinalis associated with lenvatinib during thyroid cancer treatment: a case report.

BACKGROUND: Pneumatosis intestinalis is a rare disease characterized by gas-filled cysts within the submucosa or serosa of the intestinal tract. In recent years, pneumatosis intestinalis was reported in patients undergoing cancer treatment, and some case reports exist that report that pneumatosis intestinalis occurs during administration of vascular endothelial growth factor inhibitors, such as bevacizumab and sunitinib. Here, we report the first case of pneumatosis intestinalis during lenvatinib treatment. CASE PRESENTATION: A 77-year-old Japanese man presented to our hospital with a chief complaint of numbness in the right leg and weakness of the lower limbs 9 years after right thyroid lobectomy. Computed tomography showed a tumor 90 mm in size from the lumbar spine to the sacrum, causing spinal cord compression. Blood tests showed that the patient's thyroglobulin level was increased to 11,600 ng/ml. We diagnosed him with thyroid cancer with bone metastases. External beam radiotherapy (39 Gy/13 Fr) was performed on the bone metastases, followed by total thyroidectomy and radioactive iodine therapy. Four months after radioactive iodine therapy, lenvatinib was introduced because the symptoms of numbness and weakness recurred. Lenvatinib was introduced at dose of 24 mg, and then it was reduced to 14 mg owing to Common Terminology Criteria for Adverse Event grade 3 paronychia of the right foot. Although no further significant adverse events occurred, a scheduled computed tomography image showed pneumatosis intestinalis of the ascending colon 14 weeks after the introduction of lenvatinib. No abdominal or digestive symptoms were observed; therefore, we selected conservative treatment. We discontinued lenvatinib for a week, but we were required to restart lenvatinib as the numbness in the right leg worsened after withdrawal. Since the introduction of lenvatinib, 3 years and 5 months passed; we continued lenvatinib treatment, and the therapeutic effect remains partial response. There has been no recurrence of pneumatosis intestinalis. CONCLUSIONS: Although rare, it is important to recognize that pneumatosis intestinalis can occur in association with lenvatinib and should be differentiated from intestinal perforation. Pneumatosis intestinalis association with lenvatinib can be improved by withdrawal.

A case of the accumulation of 131-iodine in the mammary gland after remnant ablation for papillary thyroid carcinoma on lactating period.

The accumulation of 131-iodine is known to occur in the extrathyroidal tissues, such as the salivary glands and the gastrointestinal tract during radioactive iodine therapy. It is considered to be due to the expression of sodium iodide symporter. A 36-year-old lactating female was treated for remnant ablation for papillary thyroid carcinoma (pT1bN1bM0 pStage I) on the condition that she refrained from breastfeeding and was separated from her child and was milked to promote the excretion of 131-iodine until the accumulation disappeared on scintigram imaging. Scintigram showed the decrease and disappearance of the 131-iodine accumulation and the external dose rate was measured and confirmed to have decreased on the day 7 and 14 after the treatment. In conclusion, remnant ablation may be available by milking and separation from the child for 7 to 14 days.

Thyroid-Associated Ophthalmopathy after Radioactive Iodine Therapy for Metastatic Follicular Thyroid Carcinoma.

Thyroid-associated ophthalmopathy (TAO) is an inflammation of the extraocular muscles and periorbital connective tissue caused by autoantibodies against common antigens to both the thyroid and orbit. The release of antigens and induction of hypothyroidism caused by radioactive iodine (RAI) therapy may exacerbate TAO. Here, we present the case of a 67-year-old-woman treated with RAI therapy for metastatic follicular thyroid carcinoma who presented with TAO during the course of sorafenib administration. Tg and TgAb levels were gradually decreased with sorafenib and lenvatinib treatment, and TAO was improved without any ophthalmologic treatment.

Invasive procedures in patients undergoing treatment with lenvatinib for thyroid cancer.

Lenvatinib is a multi-tyrosine kinase inhibitor that inhibits angiogenesis and is currently in use for the treatment of refractory thyroid cancer. Therapy using this agent can be prolonged in patients, although serious complications may ensue among those who require surgical procedures. To the best of our knowledge, the safety of invasive surgical procedures in patients undergoing treatment with lenvatinib has not been fully evaluated. A total of 94 patients were treated with lenvatinib for thyroid cancer between June 2015 and August 2019 at the Kanagawa Cancer Center. Of this cohort, 14 invasive procedures were performed on 11 patients. A total of 8 of these procedures were performed under local anesthesia and 6 under general anesthesia; 3 belonging to the latter group were emergency procedures. No primary wound complications were observed among the patients in the cohort; however, one case of delayed healing secondary to placement of a thoracic drain for acute pneumothorax was reported in the present study. Lenvatinib was initially discontinued in this patient, but it was reintroduced 17 days later due to hypoxemia that may have been related to lung metastases. Hypoxemia improved, although wound healing spanned 14 weeks. Therapy was discontinued prior to percutaneous endoscopic gastrostomy in a patient with local progression; while no wound complications were observed, the patient ultimately died from exacerbation of neoplastic disease. In the current study, which focused on surgical interventions performed on patients undergoing lenvatinib treatment, 1 in 14 wound complications improved conservatively. However, it is critical to recognize that disease progression may occur if drugs are withdrawn prior to performing invasive procedures.

Relationship between adverse events associated with lenvatinib treatment for thyroid cancer and patient prognosis.

Tyrosine kinase inhibitors (TKIs) were first approved for treating radioactive iodine-refractory differentiated thyroid cancer (DTC) and anaplastic thyroid cancer (ATC) 5 years ago. Among them, lenvatinib has a high response rate and has become the first-line drug for treating thyroid cancer. Although it has a high response rate, it is also characterized by a high frequency of adverse events (AEs). AEs previously reported in a phase II study occurred after the practical application of TKI therapy. However, the type and frequency of AEs that occurred were significantly different. The present study investigated the type and frequency of AEs in the real-world setting and examined their relationship with prognosis. Between June 2015 and May 2020, 111 patients (79 patients with DTC and 32 patients with ATC) were treated with lenvatinib. An investigation of lenvatinib AEs, including fatal events, revealed that fistula formation or severe tumor regrowth after the discontinuation of treatment was an AE associated with poor prognosis. In total, 11 patients with ATC (34.4%) and 7 patients with DTC (8.9%) developed skin fistula. The mortality rate among these patients was 38.9% (7/18), including three deaths caused by major bleeding and four deaths attributable to mediastinitis or pneumonia. In the DTC group, irreversible regrowth occurred in all 7 patients who required drug withdrawal because of AEs, and all patients died. Conversely, overall survival was longer among patients with DTC and hand-foot syndrome (HFS). Therefore, the present study illustrated that although lenvatinib therapy can result in severe AEs requiring dose reduction or treatment discontinuation, the HFS appearance portends a good prognosis in patients treated with lenvatinib.

Surgical indications and clinical management of benign and malignant follicular thyroid tumors: An algorithmic-based approach.

The present study retrospectively reviewed the treatment courses and results of patients with follicular thyroid tumors, including carcinomas. In the 5 year study period from April 2015 to March 2020, 797 patients with differentiated thyroid carcinoma and 128 patients with follicular tumors (FTs) received surgery or treatment for distant metastases and recurrence at the Kanagawa Cancer Center (Japan). Of these patients, 73 that were diagnosed with follicular thyroid carcinoma (FTC) were included in the present study. An algorithm used for the application of treatment strategies was assessed. The aim of the present study was to examine patients with FT or FTC who were treated at the Kanagawa Cancer Center to devise appropriate treatment strategies and to evaluate the various treatment outcomes of FTC. Pre-diagnostic serum thyroglobulin and thyroid stimulating hormone levels, follow-up and overall survival (OS) were investigated in the present study. The results revealed that OS was significantly increased in patients with minimally invasive follicular thyroid cancer (MIFTC) compared with widely invasive follicular thyroid cancer (WIFTC) (log-rank test, P=0.017). Additionally, OS was significantly higher in patients without distant metastasis at the first consultation compared with those initially diagnosed with distant metastasis (log-rank test, P=0.023). Although all patients without distant metastasis at the first consultation and those with MIFTC are alive, the 10-year survival rates were 75.3% for patients with WIFTC and 75.6% for those with distant metastasis at the first consultation. The results of the present study suggested that the prognosis of WIFTC was the worst among patients with FTC and distant metastasis, and that total thyroidectomy surgery and radioactive iodine treatment are essential. Additionally, if the disease progresses, prompt inclusion of tyrosine kinase inhibitor therapy is necessary.

Three Cases of Anaplastic Thyroid Carcinoma Transformation and Leukocytosis during Lenvatinib Treatment.

Since 2015, the cancer treatment lenvatinib has been used for patients with advanced radioactive iodine- (RAI-) refractory thyroid differentiated cancer; however, the drug's long-term effects have not been fully investigated. We report three cases in which lenvatinib treatment initially improved the patients' conditions, although they all died approximately 2 months after leukocytosis due to very aggressive disease progression with anaplastic thyroid carcinoma transformation. Serum interleukin-6 (IL-6) was elevated in all three cases, and granulocyte-colony stimulating factor (G-CSF) was elevated in two cases. The patients had a similar clinical course, with multiorgan metastasis and aggressive disease progression. Even with advanced cancer, lenvatinib has provided control of the disease. However, as long-term use of lenvatinib grows, it is possible that similar cases will increase, and we report our findings as an alert to other clinicians.

A Case of Unresectable Papillary Thyroid Carcinoma Treated with Lenvatinib as Neoadjuvant Chemotherapy.

A 75-year-old woman visited a nearby clinic with complaints of right clavicle discomfort, and she underwent diagnostic thoracoscopic lung biopsy, being diagnosed with lung metastasis and a right-upper mediastinal mass. The superior mediastinum mass was extrapulmonary and covered by the pleura, and it was not biopsied. Papillary thyroid carcinoma was diagnosed following biopsy of the lung metastasis. Only a small tumor, with a maximum diameter of 70 mm from the right neck to the superior mediastinum, in the thyroid gland invades the internal jugular vein and subclavian vein, forming a tumor embolus in the right brachiocephalic vein and reaching the vicinity of the superior vena cava. For life-saving purposes, we obtained approval from the Cancer Board of Kanagawa Cancer Center and used lenvatinib according to unresectable undifferentiated cancer IRB approval number 28-41. The tumor had shrunk after 4 months, and surgery was performed. The postoperative course has been good, and the patient is being followed up. The patient is alive three months after surgery, and lung metastases have disappeared on CT images. This case is reported as a successful case of neoadjuvant chemotherapy and interval debulking surgery.

Lenvatinib vs. palliative therapy for stage IVC anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is an orphan disease with extremely poor prognosis. In particular, unresectable stage IVC ATC is extremely difficult to treat and is associated with a survival of only a few months, even when treated with irradiation and/or chemotherapy. In 2015, lenvatinib was approved for the treatment of ATC in Japan. The aim of the present study was to evaluate the efficacy of lenvatinib for stage IVC ATC. A total of 32 patients with pathologically confirmed stage IVC ATC who were treated at the Kanagawa Cancer Center between 2011 and 2018 were included in the present study, of whom 16 patients were treated with lenvatinib (L group). The remaining 16 patients received palliative therapy (P group), of whom 7 were treated with weekly paclitaxel, 2 received external radiation for tumor reduction 5 days per week until treatment completion, and 2 underwent tracheostomy to avoid the risk of asphyxiation. The survival curves of both groups were analyzed using the log-rank test. The median overall survival time of the L and P groups was 4.2 and 2.0 months, respectively. A significant survival benefit was observed in the L group compared with that in the P group (P=0.00298). A reduction in tumor size by ≥30% (clinical partial response) within 1 month after treatment was observed in 5 patients (31.3%) in the L group and in no patients in the P group. Therefore, lenvatinib treatment yielded a median survival benefit of ~2 months compared with palliative therapy in stage IVC ATC. However, although a reduction in tumor size by ≥30% was confirmed in 5 patients who received lenvatinib treatment, 2 of those patients succumbed to massive necrosis and bleeding. These results suggest that an appropriate lenvatinib dose reduction is necessary.

[Giant Aneurysm of Sinus of Valsalva;Report of a Case].

Aneurysm of the sinus of Valsalva is a relatively rare disease. The patient was a 59-year-old female with a complaint of dyspnea. A very large extra-cardiac type aneurysm of sinus of Valsalva, 75 mm in diameter, was detected, and modified-Bentall operation (J-graft Valsalva 26 mm:Carpentier-Edwards Magna Ease 23 mm) was performed. The patient recovered uneventfully after the operation and was discharged on the 17th postoperative day.

Upregulation of IGF-I in the goldfish retinal ganglion cells during the early stage of optic nerve regeneration.

Goldfish retinal ganglion cells (RGCs) can regrow their axons after optic nerve injury. However, the reason why goldfish RGCs can regenerate after nerve injury is largely unknown at the molecular level. To investigate regenerative properties of goldfish RGCs, we divided the RGC regeneration process into two components: (1) RGC survival, and (2) axonal elongation processes. To characterize the RGC survival signaling pathway after optic nerve injury, we investigated cell survival/death signals such as Bcl-2 family members in the goldfish retina. Amounts of phospho-Akt (p-Akt) and phospho-Bad (p-Bad) in the goldfish retina rapidly increased four- to five-fold at the protein level by 3-5 days after nerve injury. Subsequently, Bcl-2 levels increased 1.7-fold, accompanied by a slight reduction in caspase-3 activity 10-20 days after injury. Furthermore, level of insulin-like growth factor-I (IGF-I), which activates the phosphatidyl inositol-3-kinase (PI3K)/Akt system, increased 2-3 days earlier than that of p-Akt in the goldfish retina. The cellular localization of these molecular changes was limited to RGCs. IGF-I treatment significantly induced phosphorylation of Akt, and strikingly induced neurite outgrowth in the goldfish retina in vitro. On the contrary, addition of the PI3K inhibitor wortmannin, and IGF-I antibody inhibited Akt phosphorylation and neurite outgrowth in an explant culture. Thus, we demonstrated, for the first time, the signal cascade for early upregulation of IGF-I, leading to RGC survival and axonal regeneration in adult goldfish retinas through PI3K/Akt system after optic nerve injury. The present data strongly indicate that IGF-I is one of the most important molecules for controlling regeneration of RGCs after optic nerve injury.